Derivatives of 2, 4b-dimethyl-1, 2, 3, 4, 4a, 4b, 5, 6, 7, 9, 10, 10a-dodecahydrophenanthrene-4-one, and process of preparing the same



United States Patent 'Q DERIVATIVES F 2,4B-Dl1\iETHYL-1,2,3,4,4A,4B,5,6,

7,9,10,10A DGDECAHYDROPHENANTHRENE-l- ONE, AND PROCESS OF PREPARING THE SAME Lewis H. Sarett, Princeton, N. J., assignor to Merck & C0,, Inc., Rahway, N. J., a corporation of New Jersey No Drawing. Application July 26, 1954, Serial No. 445,921

12 Claims. (Cl. 260-3403) This invention relates to novel polyhydrophenanthrene compounds and processes of obtaining the same. More particularly, it is concerned with new 2,4b-dimethyl-l,2,- 3,4,4a,4b,5,6,7,9,10,10a dodecahydrophenanthrene compounds having functional substituents in positions 1, 4 and 7 and an unsaturated aliphatic substituent in position 2, and methods of preparing these compounds.

This application is a continuation-in-part of my copending application Serial No. 306,509, filed August 26, 1952, and the co-pending application Serial No. 310,133, filed September 17, 1952, now abandoned.

The novel 2,4b dimethyl l,2,3,4,4a,4b,5,6,7,9,l0,10adodecahydrophenanthrene compounds of my invention which may be represented as follows:

M; 1 5 6 4b10a 1 8a o s 9 wherein R is a radical from the group consisting of keto and hydroxyl, and M is an unsaturated aliphatic hydrocarbon radical, and derivatives thereof having in place of the 7-keto group a substituent convertible to keto by hydrolysis, are useful in the preparation of other polyhydrophenanthrene compounds, and in the preparation of valuable steroid compounds.

t is an object of my present invention to provide novel 2,413 dimethyl 1,2,3,4,4a,4b,5,6,7,9,10,10a-dodecahydrophenanthrene compounds having functional substituents in positions 1, 4 and 7 and an unsaturated aliphatic hydrocarbon substituent at 02. It is a further object to provide processes for the preparation of said 2,4b-dimethyl- 1,2,3,4,4a,4b,5,6,7,9,10,10a dodecahydrophenanthrene compounds by the addition of an unsaturated aliphatic hydrocarbon substituent to 2,4b-dimethyl-l,2,3,4,4a,4b,- 5,6,7,9,l0,l0a dodecahydrophenanthrene compounds. Other objects will be apparent from the detailed description of my invention hereinafter provided.

In accordance with my invention, I have now found that the novel 2,4b-dimethyl-1,2,3,4,4a,4b,5,6,7,9,10,10adodecahydrophenanthrene compounds having an unsaturated aliphatic hydrocarbon substituent can be prepared by reactions which may be shown as follows:

Patented Get. 22, 1957 Hydrolysis (III) wherein R3 is a radical from the group consisting of keto and hydroxyl, R1 is a substituent convertible to keto by hydrolysis, M is an unsaturated aliphatic hydrocarbon radical, and X is a halogen.

In accordance with the foregoing reaction scheme, the starting dodecahydrophenanthrene compound (I) Wherein the 7-keto substituent is blocked by a group convertible to keto by hydrolysis, is reacted with a monohalide derivative of an unsaturated aliphatic hydrocarbon in the presence of an alkali metal or a metal alkoxide to form the corresponding compound (11) having an unsaturated aliphatic hydrocarbon radical in the 2-position. This product on hydrolysis with acid forms the corresponding compound having a free keto group in position 7 (III).

The process of introducing an unsaturated aliphatic hydrocarbon substituent in the 2 position is most conveniently effected by reacting the starting material with an unsaturated aliphatic hydrocarbon halide in the presence of an alkali metal or a metal alkoxide in a suitable inert organic solvent. Alkali metals, such as potassium or a potassium-sodium alloy, and metal alkoxides, such as potassium tertiary butoxide, sodium tertiary butoxide, sodiummethylate, potassium methylate, sodium ethylate, aluminum tertiary butoxide, aluminum isopropoxide, and the like can be used in this reaction. Inert organic solvents such as benzene, toluene, xylene, dioxan, and the like are suitable reaction mediums for carrying out this condensation.

In carrying out this reaction, I find that it is generally desirable to use an iodide derivative of the unsaturated aliphatic hydrocarbon since the use of the iodide compounds usually results in the obtainment of maximum yields of the desired products under optimum conditions, although other haldies such as the bromide and chloride can also be used. Uusally, I find it desirable to employ an amount of the halide in excess of that theoretically required to obtain maximum yields of the desired condensation products.

Thus, in accordance with my present invention the dodecahydrophenanthrene compounds can be reacted with an unsaturated aliphatic hydrocarbon halide to form the corresponding dodecahydrophenanthrene having the unsaturated aliphatic hydrocarbon radical in the 2 position. For example, the dodecahydrophenanthrenes can be reacted with a methallyl halide, an allyl halide or a propargyl halide to form the corresponding Z-methallyl, 2-ally1 and 2-propargyl derivatives, respectively.

The processes of my invention, and, in particular, certain preferred embodiments thereof can be further illustrated by the application of these processes to the preparation of specific products. Thus, the Z-methallyl derivatives of 2,4b-dimethyl-7-efnylenedioxy-1,2,3,4,4a,4b,5,6,7, 8,10,10a-dodecahydrophenanthrene-1,4-dione and 2,4b-dimethyl-7-ethylene-dioxy 1,2,3,4,4a,4b,5,6,7,8,l0,10a dodecahydrophenanthrene-4-ol-l-one are conveniently prepared by reacting the 2,4b-dimethyl-7-ethylenedioxy-1,2,3- 4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene dione or olone with an excess of methallyl iodide in the presence solvent such as alcoholor ether, The 2-allyl and 2- propargyl derivatives can be prepared and isolated in the same manner using allyl iodide and propargyl iodide in place of methallyl iodide.

Thederivatives of 2,4b-dimethyl-7-ethylenedioxy-1,2,3,-

4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 1,4 a.

an unsaturated aliphatic hydrocarbon radical substituent in thelposition can be cleaved by hydrolysiswithacids, or substances givingrise to acids, to convert'the-ethylene- 'dione or the corresponding 4-o'l-l one compound having l dioxy. substituent to a keto substituent, and cause a shifting of the double bond to the 8;'8a position; For ex- .ample, upon .hydrolyzing 2,4b-dimethyl-Z-methallylJ-eth- 'ylene dioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophe nanthrene-lA-dione with acid the 'ethylenedioxy'substituent is. cleaved and thedouble bond in position 8 a; 9 is shifted to the 8, 8a position forming 2,4b-dimethyl-2- methallyl -"1,2,3,4,4a,4b,5,6,7,9,10,10a dodecahydrophe nanthrene-1,4,7-trione. V n n t The processes 'of the V presentdnvention"have; been specifically described andillustrated above by the application to dodecahydrophenanthrene compounds wherein the 7-keto substituent is blocked or protected by the'ethylenedioxy substituent. In place of using such 7-ethylenedioxy do'decahydrophenanthrene compounds, the methods-of myinvention can be used employing as starting materials dodecahydrophenanthrene compounds having other protectingIgro'ups which can be cleaved by hydrolysis to form the-7rketo conipouhd- Thug-derivatives of the dodecahydrophe'nanthrene compounds wherein-the 7-keto' group is blocked or protected by the formation of an enoliether, 1

a cyclic. ether, or another ketal sub stituent, and the like can be used in place 'of the 7-ethylenedioxy compounds. For example, enol ether derivatives of the formula wherein Rs'is the same as defined above and R4 a hydrocarbon radical, are suitable starting'materials in our process. The methyland ethyl enol ethers which are readily prepared are particularly suitable as starting materials. Cyclic ketal derivatives, such as the 7-,eth-

, ylenedioxy derivative ofthe formula .C PT V a the corresponding monothio ketal derivative of'the for dehydrocorticosterone and ula ou -s CHz-S wherein R3 is the same uas defined above, are also useful in our process of introducing the 4b-methyl substituent. Similarly, other cyclic ketal derivatives such as the trimethylene, propylene, and butylene ketals, can be used to protect the 7-keto substituentL Upon hydrolyzing these enol ether and ketal derivatives with acid, the protecting substituent is cleaved and thefZ-keto compound having a double bond in position 8,8a is obtained.

The novel dodecahydrophenanthrene compounds 'hav- 'ing a lower alkylene orlower alkinet substituent in the 2 position prepared in accordance with this invention are useful in the field of pharmaceuticals. These unsaturated aliphatic hydrocarbon substituents after suitable modifica- 7 tion provide a side chain whichfcan be treated -to efiect progesterone and the like by total synthesis. For example, 2-methallyl-2,4b dimethyl7-ethylenedioxy1,2,3,4, 4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-1,4 dione can be converted to the valuable adrenal hormones, 11 v V cortisone in accordance with the following procedures:

Condensation of, 2-methallyl-Z,4b-dimethyl-7-ethylenedioxy 1,2,3,4,4a,4b ,5 ,6,7,8,10,1.0a; dodecahydrophenanthrene-1,4-dione with ethoxyacety lene magnesium bromide yields 2,4b dimethyl 21- methallyl 1 ethoxyethinyl 7 ethylenedioxy, -.'"'1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanth rene 1 ol 4 one, M. P, 131- 132C. -When'this ethoxyethinyl compound is treated with dilute sulfuric acid, 2,4b dimethyl L 2 methallyl M. P; 212-214 C. is obtained which on equilibration with 1 carboethoxy methylene 7 ethylene dioxy 1,2,3, 4,4a,4b,-5,6,7,8,10,1 0a dodecahydrophenanthrene 4- one, M.'P. 94-96 C. is obtained. Upon hydrolyzing this compound with alkali the corresponding free acid, M. P. 203-205 C. is produced. Reduction of this keto acid with sodium'borohydride to the 4-hydroxy acid, followed by reduction of the conjugated double bond withpotassium ammonia isopropyl alcohol aifords 2,4b di-' 'methyl 1.- carboxymethyl 2 methallyl 7 ethylenedioxy- 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4 ol, M. P. 255257 C. Reduction of this:

carboXymethyl compound with lithium aluminum hydride yields the corresponding 1 (5 hydroxyethyl) derivative M. P. 199-201 C. and 21021l C., which on reaction with p-toluene sulfonyl chloride'in the presence ofpyridine gives the 1.- ([3 toluene sulfonate), M. P. 157 -.158 C. Successive oxidations of this monotosylate derivative with the chromium trioXide-pyridine 'complex, with osmium tetroxide and with periodic acid yields 2,4b-dimethyl 118 8 p .toluenesulfonyloxyethyl) 2 ace tonyl:-7 ethylenedioxy 1,2,3,4,4a,4b, 5,6,7,8,10,1021

dodecahydrophenanthrene -'4 one, M. P. 105-108" C.

Upon reactingthis product with sodium methoxide d1.- 3 ethylenedixy A 17oz pregnene 11, 20 dione,

alkali gives the 3 ethylene dioXy derivative of dl 1l keto progesterone, M. P. 181.182.5 C. Acid hydrolysis of this product affords dl 11 ketoprogesterone. Re-

action of the 3 ethylenedioxy derivative of dl 11 keto- V progesterone with an oxalyl ester yields the corresponding 21 oxalyl ester compound which on hydrolysis is converted to the free acid. Resolution of the dl 21. oXalyl gamma acid by means of the strychnine salt followed by hydrolysis of the oxalyl acid group gives 3 ethylenedioxy A pregnene 11,20 dione, M. P. 175176.5 C. which on hydrolysis with acid afiords 11 ketoprogesterone, identical with material prepared from natural sources. dination and acetoxylation of the 21 oxalyl acid of 3 ethylenedioxy A pregnene 11,20 dione obtained as described above yields successively crystalline 3 ethylenedioxy 21 iodo A pregnene 11,20 dione and 3 ethylenedioxy A pregnene 2- ol 11,20 dione acetate, M. P. 193.5194 C. Acid hydrolysis of this latter compound yields 11 dehydrocorticosterone identical with the product obtained from natural sources. Conversion of the 3 ethylenedioxy A pregnene 21- 01 11,20 dione acetate to the cyanhydrin, M. P. dec..220224 C., and dehydration of this product gives the A 20 cyanopregnadiene, M. P. 203 C. which on oxidation with potassium permanganate yields 2-ethylenedioxy A pregnene 17,21 diol 11,20 dione acetate, dec. 262267 C. Acid hydrolysis of the latter compound yielded cortisone acetate. These reactions are described in the publication entitled Stereospecific Total Synthesis of Cortisone which appeared in the Journal of the American Chemical Society, volume 74, pages 4974- 4975.

Alternatively, following procedures described in detail in co-pending application Serial No. 310,133, 2,4b dimethyl 1 carboxymethyl 2 methallyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4 01, which can be prepared as described above, can be converted to dl 11 ketoprogesterone as follows: 2,4b dimethyl 1 carboxymethyl 2 methallyl 7 ethylene dioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene 4 -ol is reacted with an oxidizing agent to produce the corresponding 4-keto compound which is then reacted with an esterifying agent to form the corresponding 2,4b dimethyl 1 carboalkoxymethyl 2 methallyl 7 ethylenedioxy 1,2,3,4,4a,4b, 5,6,7,8,10,10a dodecahydrophenanthrene 4 one. Reaction of this compound with ozone followed by hydrolysis of the ozonide results in the obtainment of 2,4bdimethyl 1 carboalkoxymethyl 2 acetonyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4 one. The latter compound is reacted, under substantially anhydrous conditions, with a strong alkali thereby forming A 3 ethylenedioxy 11,16,20- triketo pregnene. The A 3 ethylenedioxy 11,16,20- triketo-pregnene is reacted with an organic sulfonyl halide thereby forming the corresponding sulfonate ester of A 3 ethylenedioxy 11,20 diketo 16 hydroxypregnadiene, which is reacted with hydrogen in the presence of a hydrogenation catalyst to produce A 3 ethylenedioxy 11,20 diketo pregnene. The A 3 ethylenedioxy 11,20 diketo pregnene is then reacted with an aqueous mineral acid solution whereupon the ethylenedioxy substituent attached to the 3-carbon atom is hydrolyzed and, at the same time, the double bond shifts from ring B to ring A to form A 3,11,20 triketo pregnene. The compounds of our invention having a 4-hydroxy substituent can be readily oxidized by treatment with an oxidizing agent such as pyridine-chromium trioXide' complex to convert this substituent to a keto group.

In somewhat similar manner, the corresponding 2-allyl and 2-propargyl compounds obtained in accordance with the present invention can be converted to valuable steroids. For example, following the procedures described above, 2,4b-dimethyl-2-allyl-7-ethylenedioxy-1,2,3,4,4a,4b 5,6,7,8,10,10a-dodecahydrophenanthrene 4 ol-l-one can be converted to the tosylate derivative of l-(fi-hydroxyethyl) 2,4b-dimethyl-2-allyl-7-ethylenedioxy 1,2,3,4,4a, 4b,5,6,7,8,l0,10a dodecahydrophenanthrene 1,4-dione. The 2-allyl substituent of this product can then be converted to obtain the corresponding 2-(flgy-dihydroxypropyl)compound which can be selectively esterified to form y -rnenoester. Oxidation of this monoester afiords the over activated alumina.

corresponding substituted acetonyl compound which can be converted to. the cyclized product, the ester of the 20- keto-21-hydroxy pregnene. The pregnene compound so obtained can then be converted to other valuable steroid compounds following the methods described above.

Similarly, the 2-propargyl compound of the present invention can be selectively hydrogenated to obtain the 2-allyl compound which can then be converted to valuable steroids by the above described procedures.

The following examples illustrate methods of carrying out my invention.

EXAMPLE 1 Preparation of 2,4 b-dimethyl-Z-methallyl-7-ethylenedioxy- 1 ,2,3,4,4a,4b,5,6,7,8,1 0,10a dodecahydroph enanthrene- 1 ,4-di0ne A solution of 304 mg. of 2,4b-dimethyl-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenan threne-1,4-dione (M. P. 149150.5 C.) which may be prepared as described in copendiug application Serial No. 401,705, filed December 31, 1953, in 3.0 cc. of dry benzene was treated with 0.3 cc. of methallyl iodide and then with 1.2 cc. of tertiary butyl alcohol containing 40 mg. of dissolved potassium. After standing in a stoppered flask at room temperature for one hour,'the mixture was poured into water and extracted with ether. Evaporation of the ethereal layer gave a residue of crude 2,4b dimethyl-Z-methallyl-7-ethylenedioxy-1,2,3,4,4a,4b, 5,6,7,8,10,10a-dodecahydrophenanthrene-1,4-dione which could be purified by adsorption on acid-washed alumina followed by eluation with a petroleum ether-ether mixture. it Was a colorless oil, soluble in warm petroleum ether.

EXAMPLE 2 Preparation of 2,4b-dimethyZ-Z-methallyl-7-ethylenedioxy J,2,3,4,4a,4b,5,6,7,8,10,10a -dodccaltydrophenanthrene- 1,4-di0ne A solution of 16.0 g. of 2,4b-dimethyl-7-ethylenedioxy- 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene1,4- dione (M. P. 149-1505 C.) in 190 cc. of benzene was concentrated to cc. to insure dryness. The solution was then placed under nitrogen and treated successively with 16.0 cc. of methallyl iodide and 70 cc. of tertiary butyl alcohol containing 2.31 g. of dissolved potassium. After standing at room temperature for three hours, the mixture was poured into ether, washed with water, concentratedto dryness and purified by chromatography Elution of the alumina with an ether-petroleum ether mixture yielded 2,4b-dimethyl-2- methallyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,IOa-do decahydrophenanthrene-1,4-dione (M. P. 107 0).

Another isomeric form of this compound having a melting point of 139 C. was also recovered from the chromatographic column.

Upon treatment with acid, these products are hydrolyzed to the 2,4b-dirnethyl-2-methallyl-1,2,3,4,4a,4b,5,6,7, 9,10,10a dodecahydrophenanthrene 1,4,7-trione compounds.

Th e same methallyl substituted products are obtained when -ariy of the three isomeric forms of 2,4b-dimethyl-7- ethylenedioxy T4 1,2,3,4,4a,4b,5,6,7,8,10,1'0a" doclecahydrophenanthre'ne-lA-dione described in" copeuding applicationSerial No. 401,705, or mixtures of these isomeric forms, are employed as starting materials in'the foregoin" example; 1 I a EXAMPLES U Preparation ,of 2,4b-dimethyl -2-methallyl-7-ethylendioxy- 1;2,3,4,4a,4b,5,6,7,8,10,10a dodecahydfophenant'hrene- A solution of 2.15 g. of 2,4b-dimethyl-7-ethylene-dioxy- 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4-ol-l-one (M. P. 186-'189 C.), which can be prepared as described in: copendingapplication Serial No. 401,705, filed December 31'," 19-53, in 25. cc. of benzene was concentrated to 21 cc. A mixture of 2.0 cc. of benzene and 14.0 cc. of tertiary butyl alcohol'containing 466 mg. of a dissolved potassiuruwas then added, followed by 2.0 cc. of methallyl iodide. The stoppered flask was held at 35 C. for twenty minutes. 7 The mixture was then poured into ether, washed with water and concentrated to dryness. Crystallization of the residuelfrom ether or alcohol gave 2 ,4b dimethyl 2 methallyl 7 ethylenedioxy 1,2,3,- 4, 4a,4b,5, 6, 7, 8, 10, a-dodecahydrophenanthrene 4 01-1-one, M. P. l66-168 C. l

Upon hydrolyzing this productwith acid 2,4b-dimethyl- 2 methallyl 1,2,3,4,4a,4b,5,6,7,9,10,10a dodecahydrophenanthrene-4-o1-1,7-dione is obtained.

EXA PL 4 2,41 {dimethyl 2 allyl 7 thy lenedz'oxy -1,2,3,4,4a,- '4b,5, 6,7,8,1 0,10a dode cahydrophenanthrene'- 4 o1 I-one V i i e a To 4.0 g. of 2,4b-dimethyl-7-ethylenedioxy-1,2,3,4,4a,- 4b,5,6,7,8,l0,10a dodecahydrophenanthrene 4 01 l one, dissolved in 50 ml; anhydrous benzene, was added ml. of a l M solution of potassium t-butoxide in t-butyl alcohol and 3' ml.'of allyl iodide. The solution was allowed to stand at'room temperature for one hour, after i which time ice Water was added. The mixture was then yl 2 ally1 P 1,2,3,4,4a', 4b,5,6,7,9,10,10a dodecahydro phenanth'rene-4-c1-1,7-dioue.

.In ajsimilar,manner,.:2,4b-dimethyl-2-allyl-7ethylene 7 dioxy 1,2,3,4,4a,4b,5,6,7,8,10,1021 dodecahydrophenanthrene-lA-dione is obtained by reacting"2,4bdimethyl-7 ethylenedioxy l,2,3,4,4a,'4b,5,6,7,8,10,10aj dodecahydro phenanthrene-1,4-dione with allyl iodide in the presence of 1 potassium t-butoxide. j Hydrolysis of this "product with acid yields 2,4b-dimethyl-2-ally1-1,2,3,4,4a,4b,5,6,7,9,10,- 10a dodecahydrophenanthrene-,1,4,7-nic e.

2-' v r 3,4,4a,4b,5,6,7,8,10,10adodecahydrophnanthrene 4 i ol-l-onein 25 rnlg'of; benzenelandfi'fijl of'l M potassiuni tertiary butoxide was treated with 1.7 nil of prppargyl iodide' After standing a few minutes at room temperature, a finely; divided precipitate of potassium iodide separated from thefreaction mixture.{After-'24 hours at 'room te'm per a ture, waterway added and the o'r'gaiciic' material extracted'v'vithiether. Theethereal solution was evaporated to dryness and the residue chromatographed on alumina. Consecutiyefractions offtheieluate;(petroleum ether: ether)" yield two isomeric forms of 2,4b-dimthyl-2- proparjgyl 7 'ethylehedioxy-1,Z,,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-ol-l-one melting at 'C. and l26-l28 C respectively; Hydrolysis of these' com pounds with acid yields th'etwo isomeric 2,4b-dimethyl-2- propargyl 5 1,2,3,4,4a,4b,,6;7,9;10,10a"- dodecahydrophe- Asse sor 2 g of2,4b diniethyl-7-ethylenedioxy 1 nanthrene-4 ol-1,7 diones. .7 I a In similar mariner; 2,4b-din1ethyl-2-propargyl-7-ethylenedioxy 1,2,3,4,4a,4b, 5,6,7,8, 10,1021 dodecahy'drophenanthrene lA-dione is'obtained by-reac'ting' 2,4b-dimethyl-. 7 ethylepedioxy 1 ,2,3,4,4a',4b,5 ,6,7,8,10,10a dodecahydrophenanthrene-1,4 dione with propargyl iodide inthe presence L ofpotassium t-butoxidei Hydrolysis of this product with acid yields 2,4b-dimethyl-2 prop argyl-1,2,3, 4,4a,4b,5 ,6,7,9,'10,10a dodcahydrophenanthrene 1,4,7- tn'one."-' The 2,4b} 'dimethyl-1,2,3,4,4a,4b,5 ,6,7,9, 10,10a-dodecahydrophe'nan'threne 1,4,7 trione and'the 2,4b dimethyl- 1,2,3,4,4a,4b,5,6,7,9,l0,10a dodecahydrophenanthrene-4- ol-l,7 -dione and the 7-ethylenedioxy derivatives thereof utilized as-starting materials in this invention canbe prepared as described in' the copending application SeriolNo. 401,705, filed December 31, 1953. 'Ihus',the'7-ethylenedioxy derivatives of 2,41) dimethyl 7 1,2,3,4,4a,4b,5,6, 7,9,10,10a-dodecahydrophenauthnne:1,4,7-trione V and the corresponding 4- o1-1,7-dione compound can be prepared asfollows: a fl-Ethoxy-propionaldehyde is' reacted with-ethyl magnesium bromide to produce l-ethoxy 3-hydroxy-pentane' which is oxidized with chromic acid to form 1-ethoxy-3- keto-pentane. Upon reactingthis compound with ethyl orthoforrnate in alcohol solution containing a trace of.

lithium aluminum hydride afliords the corresponding diol,

5 methyl? 6 ethoxy l;2, 3,4,4a,5,8,8a octahydro-- naphthalene-lA-diol. Upon reacting thi s'compound with dilut i acetic acid, '5-methyl-6-ketoperhydronaphthalenenaphthalene is condensediwith methyl vinyl ketone in an alkaline reaction: medium '7-keto=4b-nithyl-1-;2,3,4,4a,4b,'

5,6,7,9,l0,10a dodeeahydrophenanthrene-l,4-diol is obtained. Upon reacting the latter product with ethylene glycol in the presence of p-toluene sulfuric acid the corresponding 3 ethylenedioxy derivative, 4b methyl 7- ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a, dodecahydrophenanthrene 1,4 diol is obtained. oxidizing this compound by reaction with aluminum isopropoxide in the presence of cyclohexanone forms a mixture containing 4b methyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7, 8,10,10a-dodecahydrophenanthrene 14 dione and the corresponding 4-ol-1-one compound which can be separated and recovered by fractional crystallization and/or chromatography. The products so obtained can be con- Verted to the corresponding 2,4b-dimethyl compounds by first reacting the compounds with methyl formate in the presence of sodium hydride to obtain the 2-formyl derivatives, then reacting the formyl derivatives with methyl iodide in the presence of anhydrous potassium carbonate to produce the 2-formyl-2-methyl derivatives, and finally subjecting these latter derivatives to hydrolysis by chromatography over alkaline alumina to obtain respectively, 2,4b dimethyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8, 10,10a dodecahydrophenanthrene 1,4 dione and the corresponding 4-ol-1-one compound.

Similarly, upon reacting 7-keto-4b-methyl-1,2,3,4,4a, 4b,5,6,7,9,10,l0a dodecahydrophenanthrene 1,4 diol with an ortho ester of an alcohol, such as methanol or ethanol, in the presence of an acidic catalyst, the corresponding enol ethers are obtained which may be oxidized by reaction with aluminum isopropoxide in the presence of cyclohexanone to obtain the enol ethers of 4b methyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,9,l0, 10a-dodecahydrophenanthrene-1,4-dione and the corresponding 4-ol-l-one compound which can be separated and recovered by fractional crystallization and/ or chromatography. The latter compounds can then be converted to the corresponding 2,4b-dimethyl compounds by the methods described above.

Various changes and modifications may be made in my invention, certain preferred embodiments of which are herein described, without departing from the scope thereof. It is my intention that such changes and modifications, to the extent that they are Within the scope of the appended claims, will be construed as part of my invention.

What I claim is:

1. A dodecahydrophenanthrene compound from the group consisting of compounds of the formula:

5. 2,4b dimethyl 2 allyl 7 ethylenedioxy 1,2,3,4, 4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4 o1- l-one.

6. 2,4b dimethyl 2 propargyl 7 ethylenedioxy 1, 2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4- ol-l-one.

7. The process which comprises reacting a member from the group consisting of 7-lower alkyl-enol ether and 7-lower alkylene ketal derivatives of a compound of the formula:

wherein R is the same as defined above and M is an unsaturated aliphatic hydrocarbon radical having an unsaturated bond between carbon atoms 2 and 3.

8. The process which comprsies reacting 2,4b-dimethy1- 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-1,4 dione with methallyl iodide in the presence of potassium tertiary butoxide to produce 2,4bdimethyl 2 methallyl 7 ethylenedioxy 1,2,3,4,4a, 4b,5,6,7,8,10,10a-dodecahydrophenanthrene-1,4-dione.

9. The process which comprises reacting 2,4b-dimethy1- 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-o1-l-one with methallyl iodide in the presence of potassium tertiary butoxide to produce 2,4bdimethyl 2 methallyl 7 ethylenedioxy 1,2,3,4,4a, 4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-ol-ol-one.

10. The process which comprises reacting 2,4b-dimethy1-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-ol-l-one with allyl iodide in the presence of potassium tertiary butoxide to produce 2,4bdimethyl-2-allyl-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10, lOa-dodecahydrophenanthrene-4-01-l-one.

11. The process which comprises reacting 2,4b-dimethyl 7 ethylenedioxy-l,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-1,4 dione with allyl iodide in the presence of potassium tertiary butoxide to produce 2,4bdimethyl-2-allyl-7-ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10, l0a-dodecahydrophenanthrene-1,4-dione.

12. The process which comprises reacting 2,4b-dimethyl 7 ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4ol-l-one with propargyl iodide in the presence of potassium tertiary butoxide to produce 2,4b-dimethyl-Z-propargyl7-ethylenedioxy 1,2,3,4,4a,4b, 5,6,7,8,10,10a-dodecahydrophenanthrenei-ol-l-one.

References Cited in the file of this patent Sarett et a1.: JACS, vol. 74, pp. 4974-76 (Oct. 5, 1952). 

1. A DODECAHYDROPHENANTHRENE COMPOUND FROM THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA: 